The present invention relates in particular to the use of derivatives of cysteine for the preparation of a medicament intended to treat pathologies which result from the formation of the heterotrimeric G protein. These diseases include in particular diseases linked to the following biological functions or disorders: smell, taste, perception of light, neurotransmission, neurodegeneration, endocrine and exocrine gland functions, autocrine and paracrine regulation, arterial tension, embryogenesis, benign cell proliferation, oncogenesis, viral infection, immunological functions, diabetes, obesity, and benign and malign proliferative diseases.
The G proteins are in fact the structural association of three distinct sub-units called xcex1, xcex2 and xcex3, but operate as dissociable entities constituted by xcex1 sub-units on the one hand and xcex2/xcex3 dimers on the other hand.
The G proteins participate in the transmission of signals outside the cell thanks to its interaction with receptors with seven transmembrane domains inside using different effectors including adenylate cyclase, phospholipase C or also the ionic channels. The adenylate cyclase enzyme generates cyclic AMP (cAMP) (cf. Gilman, A. G. Biosci. Rep. 15, 65-97 (1995)). Thus, it is known that, in order to activate the adenylate cyclase, it is necessary for the G proteins to be transitionally in a heterotrimeric form, in which form the monomer constituted by an xcex1 sub-unit is associated with the dimer constituted by the xcex2 and xcex3 sub-units. It is only in this situation that the signal outside the cell can activate the a sub-unit of xcex1 G protein, which can, after disassociation, modulate the adenylate cyclase and modulate the production of cAMP.
It is also known that the xcex2/xcex3 dimers can directly activate the effectors leading to the activation of kinases regulated by extracellular signals (ERKs) or MAP kinases. A direct link between the xcex2/xcex3 sub-units and the src or src like kinases has been demonstrated (cf. Gutkind, J. S. J.Biol.Chem. 273, 1839-1842 (1998)).
Moreover, bacterial toxins such as Vibrio cholera and Bortella pertussis, peptides such as mastoparan and suramin have been presented as directly modulating the activity of the G proteins (cf. Freissmuth, M., Boehm, S., Beindl, W., et al. Mol.Pharmacol. 49, 602-611 (1996); Boehm, S., Huck, S., Motejlek, A., et al. Journal of Neurochemistry 66, 1019-1026 (1996); Cachero, T. G., Rigual, R., Rocher, A. and Gonzalez, C. Eur.J.Neurosci. 8, 2320-2327 (1996); Danilenko, M., Worland, P., Carlson, B., Sausville, E. A. and Sharoni, Y. Biochem. Biophys. Res. Commun. 196, 1296-1302 (1993); Beindl, W., Mitterauer, T., Hohenegger, M., Ijzerman, A. P., Nanoff, C. and Freissmuth, M. Mol. Pharmacol. 50, 415-423 (1996)).
For example, the choleric toxin modifies the xcex1S sub-unit of the G protein by adding an ADP-ribose originating from the NAD to an arginine-specific acceptor site. This completely blocks the activity of the GTPase, provoking persistent stimulation of its next effector, adenylate cyclase and leading to overproduction of cAMP.
The harmful effects of an abnormal cAMP level are also known and occur in particular at the level of the following biological functions or disorders: smell, taste, perception of light, neurotransmission, neurodegeneration, endocrine and exocrine gland functions, autocrine and paracrine regulation, arterial tension, embryogenesis, benign cell proliferation, oncogenesis, viral infection and immunological functions, diabetes and obesity.
The Applicant has just discovered that certain derivatives of cysteine, namely the compounds of general formula (A) 
corresponding to sub-formulae (A1) or (A2): 
in which:
X represents R12 and Y represents R8, or X and Y complete a ring with 6 members, the X-Y set representing the xe2x80x94CH(R8)xe2x80x94CH(R9)xe2x80x94 radical;
R1 represents H, a lower alkyl or alkylthio radical;
R2 and R3 represent independently H or a lower alkyl radical;
R4 represents H2 or O;
R5 represents H, or one of the lower alkyl, lower alkenyl, lower alkynyl, aryl, lower arylalkyl, heterocycle or lower alkyl heterocycle radicals, these radicals being optionally substituted by radicals chosen from the group comprising a lower alkyl radical, xe2x80x94Oxe2x80x94R10, xe2x80x94S(O)mR10 (m representing 0, 1, or 2), xe2x80x94N(R10)(R11), xe2x80x94Nxe2x80x94C(O)xe2x80x94R10, xe2x80x94NHxe2x80x94(SO2)xe2x80x94R10, xe2x80x94CO2xe2x80x94R10, C(O)xe2x80x94N(R10)(R11), and xe2x80x94(SO2)xe2x80x94N(R10)(R11);
R6 and R7 represent independently H, a xe2x80x94C(O)xe2x80x94NHxe2x80x94CHR13xe2x80x94CO2R14 radical, or one of the lower alkyl, aryl, lower arylalkyl, heterocycle or lower alkyl heterocycle radicals, these radicals being optionally substituted by radicals chosen from the group comprising the OH, alkyl or lower alkoxy, N(R10)(R11), COOH, CON(R10)(R11), and halo radicals, or R6 and R7 form together an aryl radical or a heterocycle;
R8 and R9 represent independently, H, or one of the lower alkyl, aryl, lower arylalkyl, heterocycle or lower alkyl heterocycle radicals, these radicals being optionally substituted by radicals chosen from the group comprising the OH, alkyl or lower alkoxy, N(R10)(R11), COOH, CON(R10)(R11) and halo radicals, or R8 and R9 together form an aryl radical or a heterocycle;
R10 and R11 represent independently H, an aryl radical or a heterocycle, or an alkyl, arylalkyl or lower alkyl heterocycle radical;
R12 represents NR9, S, or O;
R13 represents a lower alkyl radical optionally substituted by a radical chosen from the lower alkyl, xe2x80x94OR10, xe2x80x94S(O)mR10 (m representing 0, 1, or 2) and xe2x80x94N(R10)(R11) radicals;
R14 represents H or a lower alkyl radical;
or the compounds of general formula (B):
W1xe2x80x94Arxe2x80x94W2xe2x80x83xe2x80x83(B)
in which:
W1 represents a remainder originating from a cysteine in reduced or non reduced form;
Ar represents a radical derived from an aminobenzoic acid, the aromatic ring of which is optionally substituted;
W2 represents an amino acid, preferably an aliphatic amino acid;
or also the compounds of general formula (C): 
in which:
Z1 represents a lower alkyl radical;
Z2 and Z3 both represent H or Z2 and Z3 together form a chain having 2 to 4 elements chosen from the xe2x80x94C(O)xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH(NH2)xe2x80x94 and xe2x80x94Sxe2x80x94 radicals, it being understood that two successive elements are not both xe2x80x94C(O)xe2x80x94;
it being understood that the compounds of general formula (C) can also be presented in the form of dimers, when the Z2 radical represents a hydrogen atom which can be eliminated by oxidization;
or also a pharmaceutically acceptable salt of a compound of general formula (A), (B) or (C);
can be used to prepare medicaments intended to treat pathologies which result from the formation of the heterotrimeric G protein.
By lower alkyl radical, is understood a linear or branched alkyl radical containing 1 to 6 carbon atoms, and in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. By heterocycle radical is understood a radical constituted by one or more rings and including at least one heteroatom. By arylalkyl, alkyl heterocycle, alkylthio or lower alkoxy radical, is understood the radicals of which the alkyl radical has the meaning indicated previously.
Preferably, the Ar radical included in formula (B) is optionally substituted by an alkyl radical comprising 1 to 6 carbon atoms or an aryl radical, these alkyl or aryl radicals themselves being optionally substituted preferentially by an alkoxy radical having 1 to 4 carbon atoms, fluoro, chloro, bromo. The aryl radical preferably a phenyl can itself be substituted by an alkyl radical.
Preferably also, the compounds of general formula (B) are such that Ar represents a radical derived from an aminobenzoic acid the aromatic ring of which is substituted by a phenyl radical and W2 represents an aliphatic amino acid.
In particular, the following compounds can be used to prepare medicaments intended to treat pathologies which result from the formation of the heterotrimeric G protein:
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
1-[2(R)-amino-3-mercaptopropyl]-2(S)-n-butyl-4-(1-naphthoyl)piperazine;
bis-1,1xe2x80x2-[7-(2-amino-1-oxo-3-thiopropyl)-2-(methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine]disulphide;
bis-1,1xe2x80x2-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine disulphide;
bis-1,1xe2x80x2-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazin-7-yl)disulphide;
the compound of formula: 
the compound of formula: 
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylmethoxy)methyl-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-phenylmethoxy)ethyl-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methyoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydro-imidazo[1.2a]pyrazine, or its dimeric form;
and 7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylsulphonylethyl)-5,6,7,8-tetrahydro-imidazo[1.2a]pyrazine;
or also a pharmaceutically acceptable salt of one of these compounds.
One of the following compounds is preferably used for the invention:
bis-1,1xe2x80x2-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine disulphide (I);
bis-1,1xe2x80x2-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazin-7-yl)disulphide (II);
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine (III);
the compound of formula: 
7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine (V);
bis-1,1xe2x80x2-[7-(2-amino-1-oxo-3-thiopropyl)-2-(methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine]disulphide (VI);
the compound of formula: 
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
1-[2(R)-amino-3-mercaptopropyl]-2(S)-n-butyl-4-(1-naphthoyl)piperazine;
or a pharmaceutically acceptable salt of one of the latter.
More preferentially, one of the following compounds is used for the invention:
bis-1,1xe2x80x2-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine disulphide (I);
bis-1,1xe2x80x2-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazin-7-yl)disulphide (II);
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine (III);
7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine (V);
the compound of formula: 
or a pharmaceutically acceptable salt of one of the latter.
Finally, the following compounds are more particularly preferred:
bis-1,1xe2x80x2-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine disulphide (I);
bis-1,1xe2x80x2-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazin-7-yl)disulphide (II);
or a pharmaceutically acceptable salt of one of the latter.
The invention therefore relates firstly to the use of the compounds of general formula (A), (B) or (C) as described previously for preparing a medicament intended to treat pathologies which result from the formation of the heterotrimeric G protein. In particular, it relates to the use of said inhibitors for preparing medicaments intended to treat diseases linked to the following biological functions or disorders: smell, taste, perception of light, neurotransmission, neurodegeneration, endocrine and exocrine gland functions, autocrine and paracrine regulation, arterial tension, embryogenesis, viral infection, immunological functions, diabetes and obesity.
More particularly, the invention relates to the use of compounds of general formula (A), (B) or (C) for preparing a medicament intended to treat cholera, Acquired Immune Deficiency Syndrome (AIDS), travel diarrhea and familial masculine precocious puberty.
A subject of the invention is also new products of general formula (A) numbered 1 to 7 and described hereafter in the examples, namely:
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylmethoxy)methyl-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-phenylmethoxy)ethyl-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methyoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydro-imidazo[1.2a]pyrazine, or its dimeric form;
and 7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylsulphonylethyl)-5,6,7,8-tetrahydro-imidazo[1.2a]pyrazine.
A subject of the invention is also said new products or their pharmaceutically acceptable salts as medicaments, as well as their use for preparing a medicament intended to treat pathologies which result from the formation of the heterotrimeric G protein. In particular, it relates to the use of said products for preparing medicaments intended to treat diseases linked to the following biological functions or disorders: smell, taste, perception of light, neurotransmission, neurodegeneration, endocrine and exocrine gland functions, autocrine and paracrine regulation, arterial tension, embryogenesis, benign cell proliferation, oncogenesis, viral infection, immunological functions, diabetes, obesity, and benign and malign proliferative diseases.
The products particularly preferred for use according to the invention are therefore the following:
bis-1,1xe2x80x2-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine disulphide;
bis-1,1xe2x80x2-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazin-7-yl)disulphide;
the compound of formula: 
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylmethoxy)methyl-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-phenylmethoxy)ethyl-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methyoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine, or its dimeric form;
and 7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylsulphonylethyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;
or a pharmaceutically acceptable salt of one of the latter.
Similarly, the invention relates more particularly to the use of the compounds previously mentioned for preparing a medicament intended to treat cholera, Acquired Immune Deficiency Syndrome (AIDS), travel diarrhea and familial masculine precocious puberty.
The compounds of general formula (A) and their preparation are described in the Patent Application WO 97/30053 or in the examples hereafter. The compounds of general formula (B) and their preparation are described in the Patent Application WO 96/21456. Finally, the preparation of the compounds of general formula (C) is described in the Patent Application PCT WO 95/00497, except for the compound of formula (VII) for which the synthesis is described in the experimental part of this Application.
The pharmaceutical compositions comprising a compound of the invention can be in the form of solids, for example powders, granules, tablets, gelatin capsules, liposomes or suppositories. The appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
The pharmaceutical compositions comprising a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. The appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
The administration of a medicament according to the invention can be carried out by topical, oral, parenteral route, by injection (intramuscular, sub-cutaneous, intravenous, etc.), etc. The administration route will of course depend on the type of disease to be treated.
The administration dose envisaged for a medicament according to the invention is comprised between 0.1 mg and 10 g depending on the type of pathology to be treated.
Unless they are defined in another manner, all the technical and scientific terms used here have the same meaning as that usually understood by an ordinary specialist in the field to which this invention belongs. Similarly, all the publications, patent applications, all the patents and all other references mentioned here are incorporated by way of reference.